Combination of adrenergic receptor agonist alpha-1 or alpha-2, preferably brimonidine with fillers, preferably hyaluronic acid

ABSTRACT

A combination of a quantity of adrenergic receptor agonist α-1 or α-2, and preferably product known as brimonidine, with fillers, and preferably with hyaluronic acid, for decreasing skin or cutaneous reactions is described.

The present invention is in the surgical and dermatological domain. Thepresent invention provides a combination of quantity of adrenergicreceptor agonist α-1 or α-2, and preferably product known as brimonidinewith fillers and preferably with hyaluronic acid for decreasing skin orcutaneous reactions.

Superficial bruising and, to a lesser extent, bleeding are not uncommonconsequences (reported on average, about one-third of the time) of manyaesthetic procedures, including dermal fillers, botulinum toxins andlaser resurfacing.

More significant bruising occurs with surgical procedures such asliposuction, breast augmentations/lifts, face lifts and tummy tucks.

The management of secondary immediate reactions due to subcutaneous orintradermic injection of fillers with vascular damages or vascularbreaking wall inducing ecchymosis, bruising, leakage of blood componentshaving immediate action on inflammation setting up, redness and oedema,are of particular interest.

Although bruising and bleeding, as well as redness and erythema are notgenerally considered a big problem, most physicians prepare theirpatients for this possibility by alerting them to it prior to theprocedure. Particularly, physicians often caution against using aspirinor other anticoagulant drugs before and after the procedure, extensivelyuse ice packs immediately after the procedure and quite commonlyrecommend Arnica, an herb used to promote healing. This kind ofdrawbacks may discourage some patients and particularly towardsaesthetic procedures. In particular with regards to the consequences ofBruising/Bleeding, Physicians report that one of the most significantconcerns for patients is the amount of “downtime” and when bruisingoccurs, patients prefer to stay home rather than return to work andsocial activities

Therefore, there is a need for alleviating bruising/bleeding that occurduring aesthetic or surgical procedures especially when fillers areinjected.

The present invention is based on the demonstration by the Applicantthat the topical application/administration of an adrenergic receptoragonist together with aesthetic or surgical procedure, for instancefiller injection, reduces the occurrence of skin/cutaneous reactions.

The present invention provides a combination either an association ofquantity of adrenergic receptor agonist α-1 or α-2, and preferablyproduct known as brimonidine with fillers and preferably with hyaluronicacid. Said combination is topically administrated to an individual inneed.

The present invention provides the use in an individual in need, of aquantity of adrenergic receptor agonist α-1 or α-2, and preferablyproduct known as brimonidine in combination or association with fillersand preferably with hyaluronic acid. More specifically, the inventionprovides the use in an individual in need, of a quantity of adrenergicreceptor agonist α-1 or α-2, in combination or association with fillersintended for decreasing of alleviating cutaneous reactions. Inparticular embodiment, the quantity of adrenergic receptor agonist α-1or α-2, in combination or association with fillers are intended to beapplied to the skin simultaneously or one after the other, in any order,or in a sequential order and more specifically the skin application of aquantity of adrenergic receptor agonist α-1 or α-2, in combination orassociation with fillers is within a time interval of less than 1 hour,preferably less than 30 minutes, preferably less than 15 minutes, morepreferably less than 5 minutes. In preferred embodiments, the adrenergicreceptor agonist α-1 or α-2 is brimonidine combination or associationwith filler(s) or the filler(s) in combination or association withadrenergic receptor agonist α-1 or α-2 and preferably brimonidine, ishyaluronic acid.

In a most preferred embodiment the cutaneous reactions are selected fromthe following: bruising, bleeding, ecchymosis, erythema, oedema,necrosis, ulceration, swelling and/or inflammation.

The present invention provides a kit of part combining or associating aquantity of adrenergic receptor antagonist α-1 or α-2, and preferablyproduct known as brimonidine with fillers and preferably with hyaluronicacid. Said quantity of adrenergic receptor antagonist α-1 or α-2 is in aform of a topical composition or formulation.

The invention provides also a method for diminishing or decreasing oravoid bruising and, to a lesser extent, bleeding and particularly inaesthetic procedures, including dermal fillers and preferably hyaluronicacid, Botulinum toxin and laser resurfacing, by providing to anindividual in need thereof a quantity of adrenergic receptor agonist α-1or α-2, and preferably product known as brimonidine.

In another embodiment, the invention provides a method for alleviatingor decreasing cutaneous reactions and particularly in aestheticprocedures, including injection of dermal fillers and preferablyhyaluronic acid, Botulinum toxin and laser resurfacing, by providing toan individual in need thereof a quantity of adrenergic receptor agonistα-1 or α-2, and preferably product known as brimonidine. In a mostpreferred embodiment the cutaneous reactions are selected from thefollowing: bruising, bleeding, ecchymosis, erythema, oedema, necrosis,ulceration, swelling and/or inflammation.

The expression “association” of adrenergic receptor antagonist or saltsthereof with fillers means that the two active principles are formulatedseparately; or adrenergic receptor antagonist (preferably brimonidine)or the salts thereof is thus present in a first composition, while thefillers (preferably hyaluronic acid) is/are present in a secondcomposition. In the context of the invention “combination” and“association” are interchangeable.

Thus, according to a another embodiment of the invention, thepharmaceutical composition is in the form of a composition A comprisingadrenergic receptor antagonist, intended to be applied concomitantlywith a composition B comprising the filler(s). Preferably, composition Aand composition B are presented in the form of a kit, allowingconcomitant administration of the two compositions, or alternatively inthe form of a kit combining in the same presentation at least the twoproducts (compositions A and B) in two separate packages, preferably inthe form of tubes (co-packaging).

The expression “concomitant” application means that the compositions areintended to be applied to the skin simultaneously or one after theother, in any order, or in a sequential order (for example, in which theapplication of a pharmaceutical composition B comprising precedes theapplication of the pharmaceutical composition A), but within a timeinterval of less than 1 hour, preferably less than 30 minutes,preferably less than 15 minutes, more preferably less than 5 minutes oreven less than 1 minute.

The present invention provides a method for diminishing or decreasing oravoiding bruising and, to a lesser extent, bleeding and particularly inaesthetic procedures, including dermal fillers and preferably hyaluronicacid, Botulinum toxins and laser resurfacing, by providing to anindividual in need thereof a quantity of adrenergic receptor agonist α-1or α-2, and preferably product known as brimonidine.

As it is well known in the art, adrenergic receptors encompass both αand β receptors. Among α (also noted a-) adrenoreceptors, α1 and α2receptors were distinguished in the 1970's. During the same decade, α2receptors were found to occur on vascular smooth muscles and exhibitmediation of vasoconstrictor response (“Subtypes of functional α₁- andα₂-adrenoceptors” J R Docherty; European Journal of Pharmacology 361(1998) 1-15). Thus, molecules exhibiting α adrenergic agonism,advantageously α2 adrenergic agonism, possess peripheralvasoconstrictive activity.

Among the α receptors, the agonist can be an agonist of both α1 and α2receptors, or can be specific for α1 or α2. Preferably, the chosenmolecule displays more affinity for the α2 than for the α1 receptor, andwill generally be named, in the rest of the application, “an α2adrenergic receptor agonist”

Agonists of the a-2 adrenoceptors have been used therapeutically for anumber of conditions including hypertension, congestive heart failure,angina pectoris, spasticity, glaucoma, diarrhea, and for the suppressionof opiate withdrawal symptoms (J. P. Heible and R. R. RuffoloTherapeutic Applications of Agents Interacting with a-Adrenoceptors, p.180-206 in Progress in Basic and Clinical Pharmacology Vol. 8, P. Lomaxand E. S. Vesell Ed., Karger, 1991). Adrenoceptor agonists such asclonidine have been primarily used orally, though a patch formulation isknown. The a-2 agonists are known to mediate vasoconstriction both inthe core and periphery of a patient. In particular a-2 adrenoceptoragonists are known to cause vasoconstriction of peripheral arterioles,in response to stimulation due to cold or stress.

The most preferred compound is(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine (commonlyreferred to as brimonidine) and pharmaceutically acceptable saltsthereof, particularly the tartrate salt.

Other compounds of the invention include naphazoline, tetra-hydrozaline,oxymetazoline, xylometazoline, epinephrine, norepinephrine,phenylephrine and methoxamine and their pharmaceutically acceptablesalts.

A number of patents describe the use of brimonidine for treatingophthalmic conditions and eye diseases. In Canadian patent CA2326690,there is described the use of topical ophthalmic preparations for useonly in the eyes, to treat eye diseases.

In one embodiment, the compounds of the invention are administrated to apatient in need thereof topically. Therefore, in the context of theinstant invention the compounds are delivered to the affected area ofthe skin in a pharmaceutically acceptable topical carrier. As usedherein, a pharmaceutically acceptable topical carrier is anypharmaceutically acceptable formulation that can be applied to the skinsurface for topical, dermal, intradermal, or transdermal delivery of apharmaceutical or medicament. The combination of a pharmaceuticallyacceptable topical carrier and a compound of the invention is termed atopical formulation or topical composition of the invention.

Topical formulations of the invention are prepared by mixing a compoundof the invention with a topical carrier according to well-known methodsin the art, for example, methods provided by standard reference textssuch as, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591,1672-1673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.;et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), both ofwhich are hereby incorporated herein by reference.

The topical carriers useful for topical delivery of compounds of theinvention can be any carrier known in the art for topicallyadministering pharmaceuticals, for example, but not limited to,pharmaceutically acceptable solvents, such as a polyalcohol or water;emulsions (either oil-in-water or water-in-oil emulsions), such ascreams or lotions; micro emulsions; gels; ointments; liposomes; powders;and aqueous solutions or suspensions.

In a preferred embodiment, the topical carrier used to deliver acompound of the invention is an emulsion, gel, or ointment. Emulsions,such as creams and lotions are suitable topical formulations for use inthe invention.

An emulsion is a dispersed system comprising at least two immisciblephases, one phase dispersed in the other as droplets ranging in diameterfrom 0.1 mu m to 100 mu m. An emulsifying agent is typically included toimprove stability.

When water is the dispersed phase and an oil is the dispersion medium,the emulsion is termed a water-in-oil emulsion.

When an oil is dispersed as droplets throughout the aqueous phase asdroplets, the emulsion is termed an oil-in-water emulsion.

Emulsions, such as creams and lotions that can be used as topicalcarriers and their preparation are disclosed in REMINGTON: THE SCIENCEAND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro ed. 19th ed. 1995,hereby incorporated herein by reference.

In another embodiment, the topical carrier used to deliver a compound ofthe invention is a gel, for example, a two-phase gel or a single-phasegel. Gels are semisolid systems consisting of suspensions of smallinorganic particles or large organic molecules interpenetrated by aliquid. When the gel mass comprises a network of small discreteinorganic particles, it is classified as a two-phase gel.

Single-phase gels consist of organic macromolecules distributeduniformly throughout a liquid such that no apparent boundaries existbetween the dispersed macromolecules and the liquid. Suitable gels foruse in the invention are disclosed in REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY 1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995),hereby incorporated herein by reference. Other suitable gels for usewith the invention are disclosed in U.S. Pat. No. 6,387,383 (issued May14, 2002); U.S. Pat. No. 6,517,847 (issued Feb. 11, 2003); and U.S. Pat.No. 6,468,989 (issued Oct. 22, 2002), each of which patents is herebyincorporated herein by reference.

In another embodiment, the topical carrier used to deliver a compound ofthe invention is an ointment.

Ointments are oleaginous semisolids that contain little if any water.

Preferably, the ointment is hydrocarbon based, such as a wax,petrolatum, or gelled mineral oil. Suitable ointments for use in theinvention are well known in the art and are disclosed in REMINGTON: THESCIENCE AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19thed. 1995), hereby incorporated herein by reference.

In another embodiment, the topical carrier used in the topicalformulations of the invention is an aqueous solution or suspension,preferably, an aqueous solution.

Well-known solutions and suspensions are suitable topical carriers foruse in the invention. Suitable aqueous topical formulations for use inthe invention are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OFPHARMACY 1563-1576 (Alfonso R. Gennaro ed. 19th ed. 1995), herebyincorporated herein by reference. Other suitable aqueous topical carriersystems are disclosed in U.S. Pat. No. 5,424,078 (issued Jun. 13, 1995);U.S. Pat. No. 5,736,165 (issued Apr. 7, 1998); U.S. Pat. No. 6,194,415(issued Feb. 27, 2001); U.S. Pat. No. 6,248,741 (issued Jun. 19, 2001);U.S. Pat. No. 6,465,464 (issued Oct. 15, 2002), all of which patents arehereby incorporated herein by reference.

The topical formulations of the invention can comprise pharmaceuticallyacceptable excipients such as those listed in REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995;Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS(1997), hereby incorporated herein by reference, including, but notlimited to, protectives, adsorbents, demulcents, emollients,preservatives, antioxidants, moisturizers, buffering agents,solubilizing agents, skin-penetration agents, and surfactants.

Pharmaceutical Additives

The topical formulations of the invention can include pharmaceuticals ortheir pharmaceutically acceptable salts, for example, but not limitedto, topical corticosteroids and other anti-inflammatory agents, such asbetamethasone, diflorasone, amcinonide, fluocinolone, mometasone,hydrocortisone, prednisone, and triamcinolone; local anesthetics andanalgesics, such as camphor, menthol, lidocaine, and dibucaine, andpramoxine; antifungals, such as ciclopirox, chloroxylenol, triacetin,sulconazole, nystatin, undecylenic acid, tolnaftate, miconizole,clotrimazole, oxiconazole, griseofulvin, econazole, ketoconozole, andamphotericin B; antibiotics and anti-infectives, such as mupirocin,erythromycin, clindamycin, gentamicin, polymyxin, bacitracin, and silversulfadiazine; and antiseptics, such as iodine, povidine-iodine,benzalkonium chloride, benzoic acid, chlorhexidine, nitrofurazine,benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,resorcinol, and cetylpyridinium chloride.

Dosages and dosing frequency will be determined by a trained medicalprofessional depending on the activity of the compound of the invention,the characteristics of the particular topical formulation, and theidentity and severity of the dermatologic disorder treated or prevented.

In general, a compound of the invention is present in a formulation ofthe invention in an amount of from about 0.001% to about 10% of thetotal weight of the formulation, preferably, of from about 0.05% toabout 5%, more preferably, of from about 0.1% to about 2% of the totalweight of the formulation.

Another aspect of the invention is an article of manufacture thatcomprises a topical formulation of the invention in a suitable containerwith labelling and instructions for use.

The container can be a dropper or tube with a suitable small orificesize, for instance the topical formulations of the invention can befilled and packaged into a plastic squeeze bottle or tube; or asmall-size bottle, a phial or a vial.

Preferably, instructions are packaged with the formulations of theinvention, for example, a pamphlet or package label. The labelinginstructions explain how to administer topical formulations of theinvention, in an amount and for a period of time sufficient to treat thepatient. Preferably, the label includes the dosage and administrationinstructions, the formulation's composition, the clinical pharmacology,drug resistance, pharmacokinetics, absorption, bioavailability, andcontraindications.

Fillers can be any product known by the skilled artisan and thepreferred compounds are molecules such as Hyaluronic acid, collagen,dextran sulphate, elastine, polyurethane gels, poly-L-lactic acid orcalcium hydroxyapatite or silicone or mixture thereof. The mostpreferred are compounds resorbable such as hyaluronic acid cross-linkedor linear.

Hyaluronic acid or hyaluronate is a non-sulfated glycosaminoglycandistributed widely throughout connective, epithelial, and neuraltissues. It is one of the chief components of the extracellular matrix,contributes significantly to cell proliferation and migration. It playsan important role in skin hydration and skin elasticity. The level ofhyaluronic acid decreases with ageing in quantity and quality, inducingskin drying which becomes wrinkled.

Hyaluronic acid is highly soluble in water and forms solutions with highviscosity levels. Therefore, it is widely used as pharmaceuticalproduct. The safety of this compound is considered to be very safe sinceno immunogenicity reaction has been observed. Few minor adverse eventshave been noticed.

Therefore and advantageously, the filler is hyaluronic acid or apharmaceutically acceptable salt or derivative thereof, particularly thesodium or potassium salt. Hyaluronic acid can be used under differentforms: salts thereof, derivatives thereof such as esters or amides, in alinear form or cross-linked. In particular, the molecular weight,typically comprised between 500 kDa and 5 000 kDa, and the degree ofcross-linking depends on the application, especially on the depth of thewrinkles to be filled.

According to the instant invention, the term “pharmaceuticallyacceptable salt(s)”, as used herein, means those salts of compounds ofthe invention that are safe and effective for topical use in mammals andthat possess the desired biological activity. Pharmaceuticallyacceptable salts include salts of acidic or basic groups present incompounds of the invention.

Pharmaceutically acceptable acid addition salts include, but are notlimited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate,succinate, maleat, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids.

Suitable base salts include, but are not limited to, aluminum, calcium,lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.For a review on pharmaceutically acceptable salts see BERGE ET AL., 66J. PHARM. Sci. 1-19 (1977), incorporated herein by reference.

By “pharmaceutically acceptable topical formulation” it is meant in thecontext of the invention any formulation which is pharmaceuticallyacceptable for topical delivery of the compounds of the invention.According to the invention, a topical formulation will comprise at leasta compound of the invention. The choice of topical formulation willdepend on several factors, including the nature of the symptoms to betreated or prevented, the physiochemical characteristics of theparticular compound of the invention and of other excipients present,their stability in the formulation, available manufacturing equipment,and cost constraints.

As used herein, a “therapeutically effective amount of a compound of theinvention” means the minimum amount of the compound that is effective toobtain the desired effect in the context of the invention.

As used herein, the term “subject” or “patient” are used equivalentlyand means any animal, preferably a mammal, more preferably, a human towhich will be or has been administered compounds or formulations of theinvention. The term ‘mammals used herein, encompasses any mammal.

Figures are photographs of skin treatment with brimonidine (includingboth treated (Z4) and non-treated area in the same picture (Z3) takenimmediately and 2-5 and 10 minutes after the dermabrasion.

EXAMPLES

The following examples are provided for illustrative purposes only andare not to be construed as limiting the invention's scope in any manner.

Example 1

A aqueous solution topical formulation of the invention comprises(5-Bromo-quinoxalin-6-yl)-(4,5-dihydro-IH-imidazol-2-yl)-amine-L-tartrate,(brimonidinetartrate) (0.15 wt. %); benzalkonium chloride (0.005 wt. %)as a preservative; and the inactive ingredients: boric acid; calciumchloride; magnesium chloride; potassium chloride; purified water; sodiumborate; sodium carboxymethylcellulose; sodium chloride; withhydrochloric acid and/or sodium hydroxide to adjust the pH to 5.6 to6.6. The osmolality is in the range of 250-350 mOsmol/Kg.

Example 2

A possible gel formulation of the invention is described in the Tablebelow.

Ingredients Weight % Brimonidine tartrate  1.0% Methylparaben 0.20%Propylparaben 0.05% Carbomer 934P NF  1.0% Sodium Hydroxide QS pH 7Purified Water USP QS 100%

The ingredients are mixed together and aqueous sodium hydroxide isslowly added to the mixture until a pH of about 7 is reached and the gelis formed.

Example 3 In Vivo Dermabrasion Assays in Minipig Minizone Model Using aBURANE XL Laser and Skin Interaction with Brimonidine Gel

The objectives of this study were to assess the local dermal effect ofsingle dermal application of Brimonidine Gel placebo or 1% applied ondelimited abraded mini-zone (2.8 cm² and different dermabraded skinconditions) in the Gottingen® minipig.

In the present work, the α2A-adrenoceptor (Brimonidine) which is awell-known potent vasoconstrictor* in the porcine species is evaluatedwith regards to different skin dermabrasion conditions in order toevaluate the cutaneous reactions and particularly the redness/bleedingkinetics modifications. (*): Anna Wikberg-Matsson and Ulf Simonsen,“Potent α2A-Adrenoceptor-Mediated Vasoconstriction by Brimonidine inPorcine Ciliary Arteries”, Investig. Ophth. and Visual Science. 2001;42:2049-2055

One female Göttingen® minipig (naïve), between 4 and 8 months old,received Dermal (topical) application of Brimonidine Gel at 1% ondelimited mini-zones (2.8 cm², using a Ringflost®).

On Day −1:

each zone is clipped free from hair. On the clipped area (dorsum,avoiding the spinal column and the intra-scapular area), 4 minizones (2on either side) is delimited using Ringflost® and surrounded with anindelible pen.

On Day 1:

The animal is anesthetized (Zoletil®) before dermabrasion. Each minizoneis disinfected with chlorexidine. The experimental conditions used foreach zone is set as follows:

Head Left Z1: 6.5 j/cm2, 6 passes Z3: 10 j/cm2, 6 passes Right Z2:Brimonidine gel 1% + Z4: Brimonidine gel 1% + 6.5 j/cm2, 6 passes 10j/cm2, 6 passes

The Brimonidine gel 1% is gently applied 5 minutes prior to thedermabrasion procedure.

The cutaneous reaction is evaluated immediately, and 2-5 and 10 minutesafter the dermabrasion procedure. The skin is examined to evaluate thedegree of erythema, edema, desquamation, scab formation and any otherlesions. Cutaneous reaction is evaluated according to the grading scaledescribe in “OCDE Guideline No. 404. Acute dermal irritation/corrosion”.If feasible, cutaneous reactions evaluation will be performed by thesame persons during the whole study.

The duration of treatment was one day. Thereafter each zone is coveredwith Tegaderm® dressings until complete wound healing process.

Photographs (including both treated and non-treated area in the samepicture) will be taken immediately and 2-5 and 10 minutes after thedermabrasion procedure.

These assays showed that only superficial damage is induced by theErbium laser in these conditions: depth was limited to the epidermis.All dermabrasion procedures are performed under anesthesia (Zoletil®).

Painkiller (1 mL per animal, Finadyne®) is used after the 20 minutesdermal evaluation completion.

The Laser used is Erbium Yag, 2940 nm BURANE XL from Wavelightaesthetics (Quantel)

As demonstrated by comparative analysis in the pictures between Z3 & Z4,the vasoconstrictor effect of Brimonidine being visually more evidentstarting from 5 min post-dermabrasion until 14 min and beyond since thehalf-life of brimonidine is 4 hours.

This effect was clearly visible, starting from the peripheral area(erythematic halo) and expanding until the heart of the circular area.

As conclusion, this example shows that Brimonidine is capable ofdecreasing cutaneous reactions during aesthetic or surgery proceduresand particularly of alleviating bruising or bleeding reactions.

1. A combination or association of a quantity of adrenergic receptoragonist α-1 or α-2.
 2. A method of decreasing or alleviating cutaneousreactions in an individual subject in need, the method comprisingadministering a quantity of adrenergic receptor agonist α-1 or α-2, incombination or association with fillers to the individual subject. 3.The method according to claim 2 wherein, the quantity of adrenergicreceptor agonist α-1 or α-2, in combination or association with fillersare applied to skin of the individual subject simultaneously or oneafter the other, in any order, or in a sequential order.
 4. The methodaccording to claim 2 wherein the skin application of the quantity ofadrenergic receptor agonist α-1 or α-2, in combination or associationwith fillers is conducted within a time interval of less than 1 hour. 5.The method according to claim 2, wherein the adrenergic receptor agonistα-1 or α-2 is brimonidine in combination or association with filler(s).6. The method according to claim 2, wherein the filler(s) in combinationor association with adrenergic receptor agonist α-1 or α-2 is hyaluronicacid.
 7. The method according to claim 2, wherein the cutaneous reactionis selected from the group consisting of: bruising, bleeding,ecchymosis, erythema, oedema, necrosis, ulceration, swelling andinflammation.
 8. A kit comprising a quantity of adrenergic receptoragonist α-1 or α-2 with fillers.
 9. The kit according to claim 8,wherein the quantity of adrenergic receptor agonist α-1 or α-2, is inthe form of a topical composition or formulation.
 10. A method fordiminishing or decreasing or avoiding bruising and, to a lesser extent,bleeding and particularly in aesthetic procedures, including dermalfillers and optionally hyaluronic acid, Botulinum toxin and laserresurfacing, the method comprising providing to an individual subject inneed thereof a quantity of adrenergic receptor agonist α-1 or α-2.
 11. Amethod for alleviating or decreasing cutaneous reactions andparticularly in aesthetic procedures, including injection of dermalfillers and optionally hyaluronic acid, Botulinum toxin and laserresurfacing, the method comprising providing to an individual subject inneed thereof a quantity of adrenergic receptor agonist α-1 or α-2. 12.The method according to claim 8, wherein the cutaneous reaction isselected from the group consisting of: ecchymosis, bruising, bleeding,erythema, oedema, necrosis, ulceration, swelling and inflammation. 13.The combination or association according to claim 1, wherein theadrenergic receptor agonist α-1 or α-2 is brimonidine.
 14. Thecombination or association according to claim 1, wherein the filler ishyaluronic acid.
 15. The method according to claim 4, wherein the skinapplication is conducted within a time interval of less than 30 minutes.16. The method according to claim 4, wherein the skin application isconducted within a time interval of less than 15 minutes.
 17. The methodaccording to claim 4, wherein the skin application is conducted within atime interval of less than 5 minutes.
 18. The kit according to claim 8,wherein the adrenergic receptor agonist α-1 or α-2 is brimonidine. 19.The kit according to claim 8, wherein the fillers include hyaluronicacid.
 20. The method according to claim 10, wherein the adrenergicreceptor agonist α-1 or α-2 is brimonidine.
 21. The method according toclaim 11, wherein the adrenergic receptor agonist α-1 or α-2 isbrimonidine.